The endocannabinoid (eCB) system has been implicated in a variety of processes including cell signaling, memory encoding, compensatory mechanisms, and immunosuppressant and anti-inflammatory responses. The eCB system comprises at least two receptors: the CB1 cannabinoid receptor, widely distributed in the brain, and present in some peripheral organs, and the CB2 receptor, found principally in the periphery and immune systems and in some regions of the brain. The endogenous agonists of these receptors are the endogenous cannabinoids (eCBs), a family of lipids comprising the fatty acid anandamide (AEA) as well as other fatty acids.
Endocannabinoid-degrading enzymes, including fatty acid amide hydrolase (FAAH), are responsible for cleaving and deactivating eCBs in vivo. FAAH is an integral membrane protein that is expressed in high levels in several brain regions, especially in the neurons of the hippocampus, cerebellum, neocortex and olfactory bulb. FAAH is the principal enzyme responsible for the hydrolysis of AEA in vivo and is also capable of hydrolyzing a wide variety of other substrates. It is known that inhibiting FAAH can lead to increases in fatty acids, including AEA, which could enhance cannabinoid signals within the eCB system. It has also been demonstrated that a number of fatty acid amides can induce analgesia in acute and chronic animal models of pain. Thus, increasing the level of AEA and other fatty acid amides (e.g., N-palmitoyl ethanolamide, N-oleoylethanol amide and oleamide) by inhibiting FAAH may lead to an increase in the nociceptive threshold. For these reasons, inhibitors of FAAH are useful in the treatment of pain. Inhibitors of FAAH might also be useful in the treatment of other disorders involving deregulation of the eCB system (e.g., depression, anxiety, eating disorders, gastrointestinal and cardiovascular disorders, inflammation, excitotoxic insult, brain trauma and fibromyalgia), and may avoid some of the side effects typically associated with CB receptor agonists (e.g., catalepsy or hypothermia).
In addition, previous studies have demonstrated that eCBs can control spasticity and provide neuroprotection in multiple sclerosis rodent models. Thus, certain FAAH inhibitors may be useful agents for treating symptoms or achieving disease modification changes in multiple sclerosis. There is also evidence that when FAAH activity is reduced or absent, AEA acts as a substrate for COX-2, which can convert it to a prostamide. Thus, certain prostamides may be elevated in the presence of an FAAH inhibitor. Given that certain prostamides are associated with reduced intraocular pressure and ocular hypotensivity, FAAH inhibitors may also be useful agents for treating glaucoma.